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Neuroscientists Boyden, Deisseroth and Miesenböck reflect on the
advances secured with the technique that won them the Frontiers of
Knowledge Award in Biomedicine
Optogenetics moves towards the clinic with
trials against blindness and addiction, and
promotes a deeper understanding of
memory and sleep

Optogenetics is now in widespread use to explore functions like sleep,
appetite, aggression or the reward mechanism that drives addictions.

Trials are already under way using optogenetic tools to treat the blindnesscausing disease retinitis pigmentosa, and the technique has inspired new
therapeutic strategies to combat addiction.

The presentation ceremony of the BBVA Foundation Frontiers of Knowledge
Awards will take place tomorrow in the Foundation’s Madrid headquarters.
Madrid, June 20, 2016.- Discovering the brain region that governs aggression,
identifying how and when addictions set in, so we can endeavor to control them,
or elucidating the mechanisms that regulate sleep and wakefulness. In all these
areas, neuroscience is making extraordinary strides facilitated by optogenetics, a
technique developed barely ten years ago which allows to explore the workings
of the living brain with unprecedented resolution. Its architects Ed Boyden, Karl
Deisseroth and Gero Miesenböck have been granted the BBVA Foundation
Frontiers of Knowledge Award in Biomedicine (the award was decided on
January 15 and will be presented to the three laureates at a ceremony tomorrow
in the BBVA Foundation’s Madrid headquarters).
Optogenetics, say its founders, is already edging close to the clinical research
stage. They believe that it will help not only to decipher what goes on inside the
brains of Alzheimer’s sufferers or improve the treatment of mental illness, but also
to understand the biological substrate of the personalities and emotions that
make us unique.
Optogenetics uses light (from a laser or LED source) to switch on selected groups
of neurons into which a light-sensitive protein has previously been inserted.
Although the technique has so far been confined primarily to basic research, it is
now being used for the first time in clinical trials in the United States for blindnesscausing retinitis pigmentosa, a disease that destroys photoreceptors in the
eye. The treatment under trial seeks to restore vision by using optogenetic
techniques to turn other cells in the retina sensitive to light.
Other potential trials in the pipeline draw on optogenetics to treat certain forms of
deafness and superficial pain. In these applications, and in the trial focusing on
retinitis pigmentosa, optogenetic tools are delivered into cells in the eye, ear and
peripheral nervous tissue, all of them more accessible than neurons. Optogenetics
is accordingly less invasive here than when used in the brain, something only
attempted to date in experimental animals.
Deisseroth explains the current state of play: “The closest medical applications are
those affecting the peripheral nervous system. Optogenetics could probably be
used for any condition affecting this system; for instance, to eliminate post-surgical
pain or certain types of blindness. It would be harder to apply it in processes like
Parkinson’s or epilepsy, which would require intervening in very specific, very deep
regions, and even harder in psychiatric disorders, of which we still know very little.”
Deisseroth: research into aggression “is of pressing significance in the modern
world”
Hence the laureates’ insistence that optogenetics is for the moment best
regarded as a basic science resource. “The great promise of optogenetics is to
deliver a better understanding of normal brain function,” in the view of Oxford
University professor Gero Miesenböck. “Optogenetics has catalyzed the
transformation of neuroscience from an observational to an interventionist
discipline.”
But they also share the conviction that what we are learning now will someday
serve to deliver more rational and effective therapies. Karl Deisseroth, who
combines research and teaching at Stanford University with his work as a
psychiatric clinician, remarks, for instance, that knowledge gleaned from
optogenetics is already informing clinical practice in anti-addiction therapies.
“Insights obtained using animal models have been used to guide and deliver
human therapies for cocaine and opiate addiction, with promising published
results,” he assures. Concretely, optogenetics has been employed in mice to
identify the effects of addictive behavior in a highly specific region of the brain;
then that region was treated in human patients using a noninvasive technique
known as transcranial magnetic stimulation.
Optogenetics is an increasingly important input to the development of targeted
therapies – via stimulation, conversation or pharmacological agents – for mental
illness. It has already served to pinpoint an anti-anxiety pathway in a brain region,
the amygdala, associated with fear and anxiety.
The three laureates agree that we are just scratching the surface of what the
technique can teach us about the healthy, and the sick brain. Another “striking
example” cited by Deisseroth of the promise of optogenetics is the finding that “a
very small and specific region deep in the brain powerfully modulates violent
aggression in mice.” Studying the nature of aggression, the psychiatrist believes, is
“of pressing significance in today’s world.”
Miesenböck: “We understand more and more about what regulates sleep”
Miesenböck is currently studying neural circuits that accumulate information over
time, like those governing sleep and wakefulness. “We do not know how or why
our conscious experience fades when we fall asleep. What we do understand
better and better, and where optogenetics has been helpful, is the mechanisms in
the brain that regulate sleep and waking, and how these mechanisms, for
example, prevent us from sleep-walking.”
He admits that one of his motives for developing optogenetics was to understand
“how biological matter generates moods or emotions. If playing back particular
electrical activity patterns into the brain recreated perceptions, movements,
memories, or emotions, one would have a powerful tool for discovering the neural
signals that normally underlie these aspects of our mental lives.”
Boyden: with optogenetics “you can speak the natural language of the brain”
For Edward Boyden, Professor of Biological Engineering and Brain and Cognitive
Sciences at Massachusetts Institute of Technology, the “beauty” of optogenetics is
that it allows to speak “the natural language of the brain. We can shine light on a
neuron and it will turn on within milliseconds, and after we turn the light off the
neurons will turn off within milliseconds. Thus, it is possible to control neural activity
with the natural temporal precision of the intact, behaving brain.”
The three awardees, the intellectual fathers of optogenetics, are clear about the
drawbacks to its use in human brains. The method is cumbersome and highly
invasive (insertion of a fiber optic cable that carries the light to the brain), so every
step must be taken to ensure its safety and to assess whether the value of the
information obtainable fully justifies the means.
In optogenetics, the gene that turns the neurons sensitive to light is delivered using
a viral vector. And this kind of gene therapy has posed problems of safety in the
past. Boyden, however, is optimistic: “There are many groups working on gene
therapy techniques right now, and the field, I am sure, will continue to offer better
and better methods for the delivery of optogenetic tools into living tissues and
organs.”
Boyden is currently on the lookout for technologies to map our neural wiring and
track how information flows through the active brain. The big challenge, as he
sees it, is to refine optogenetics in terms of its precision, so it is possible to control
not just small sets of neurons but single cells.
“In the brain, everything is far more complex than we think,” he observes,
reiterating that the goal in neuroscience is to achieve the greatest possible
precision. “‘Playing’ the brain is like playing the piano. Will we some day be able
to introduce information into the brain with a high degree of resolution?”
“My hope is that we will be able to control all the cells in the brain”
This would provide us with a significantly clearer picture of the high-speed
dynamics of the brain: “My hope is that in the coming decades, we will be able to
see the structure of the brain, watch it in action, and control all its individual
cells. Then we might be able to make computational models of the brain, and
understand how thoughts and feelings emerge from brain circuitry. We might
even be able to pinpoint the key sites that cause brain disorders, which in turn
would yield new, better treatments.”
Last but not least, the ethical implications of controlling behavior cannot be
ignored. Deisseroth, who sits on the advisory committee of the BRAIN initiative
(promoted by U.S. President Barack Obama), explains that “optogenetics delivers
real-time and specific control of cognitions and behaviors in studies that can
verge on the unsettling. Experimental biologists, physicians, and therapists have
long had the ability to change behavior, through genetic, pharmacological,
electrical, and environmental interventions. In that sense, optogenetics does not
raise any fundamentally new ethical or philosophical questions. But the more
precise the intervention becomes, and as our understanding of the neural circuit
control of behavior advances rapidly, these issues are worth serious discussion with
colleagues in law, ethics, philosophy, and education – indeed across all of the
humanities.”
How the microbiology of saline lakes may revolutionize neuroscience
Optogenetics arose from the linkage of several apparently unconnected findings.
The first came about in the 1970s, with the discovery of a protein in saline lake
bacteria with the ability to convert light into electricity in a single biochemical step.
In 2002, Gero Miesenböck used this protein to control cultured neurons by means
of light. To do so, he inserted its gene in the neuronal DNA, and the illuminated
cells responded like the saline lake bacteria, by firing an electrical signal.
Miesenböck’s method, however, had technical drawbacks that hindered its largescale application.
The key to a solution came to Karl Deisseroth and Ed Boyden when working
together at Stanford in the year 2004. They had heard of the discovery, one year
before, of a green alga protein similar to that of the saline lake bacteria, but with
far superior light responsiveness. The challenges were many, and today Deisseroth
and Boyden recall that they only kept going due to sheer determination and the
receipt of a grant for high-risk projects. The journals Science and Nature actually
turned down the paper presenting the technique now hailed as revolutionary by
research teams around the world.
Bio notes
Edward Boyden (Plano, Texas, United States, 1979) is a neurotechnologist. After
completing a BS in engineering at Massachusetts Institute of Technology, he
rejoined the institute in 1996 and remains there today as Professor of Biological
Engineering and Brain and Cognitive Sciences.
Karl Deisseroth (Boston, Massachusetts, 1971) studied biochemical sciences at
Harvard than went on to complete an MD and a PhD in neuroscience at Stanford
University. He combines his work as a psychiatric clinician with teaching and basic
research at Stanford, where he is currently DH Chen Professor of Bioengineering
and of Psychiatry and Behavioral Sciences.
Gero Miesenböck (Braunau, Austria, 1965) holds an MD from the University of
Innsbruck. En 1992, he began work at the Memorial Sloan-Kettering Cancer
Center in New York alongside James E. Rothman (2013 Nobel Prize in Medicine). In
2007 he moved to the University of Oxford, where he combines the post of
Waynflete Professor of Physiology with the leadership of the Centre for Neural
Circuits and Behaviour (CNBC), which he also founded.
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